tbuckley/cabot-search huggingface dataset:
Demographic comparison of survival outcomes after bone marrow transplantation in adolescent and young adult patients: A single institution cohort study.
Authors: Kimberly Helen Seymour, Hayley Brianne Flanagan, John Mariano, Andrea M. Baran, Jeffrey Robert Andolina
Journal: Journal of Clinical Oncology (2023)

e18522 Background: Bone marrow transplant (BMT) has become an increasingly common treatment modality for both malignant and non-malignant conditions. However, BMT requires significant healthcare and financial resources, which can result in allocation disparities across socioeconomic, demographic, and racial/ethnic groups. The data exploring how demographic disparities impact survival after BMT is limited, particularly within the adolescent and young adult (AYA) population, defined as patients between the ages of 15 and 39 years. The goal of this study was to assess overall survival of AYA patients undergoing transplant at our institution and to gain insight into if demographic factors impact the likelihood of mortality after transplantation. Methods: Patients aged 15-39 who underwent transplant at the Wilmot Cancer Institute in Rochester, NY between 2012-2020 were identified. Information regarding demographic characteristics, indication for transplant, and mortality was collected. The primary endpoint was overall survival (OS), defined as the time from transplant to the date of death from any cause or the date of last in-person contact. Survival criteria were estimated using the Kaplan-Meier method and compared using mortality odds ratios. These analyses were stratified by indication for transplant, recorded race/ethnicity, gender, and by age. Results: 169 patients met inclusion criteria, and median OS for the entire cohort was not reached. Of 108 allogenic transplant recipients, median OS was 7.85 years (95% CI [3.3, not estimated]). Median OS for patients receiving transplant for solid tumor pathology was 3 years (95% CI [0.4 years, not estimated]), compared to other indications for transplant where survival exceeded the median. For allogenic transplant patients, median OS for Black patients was 4.8 years (95% CI [0.7 years, not estimated]), 7.8 years for Caucasian patients (95% CI [3.3 years, not estimated]), median OS was not reached for Hispanic patients, and 1.1 years for all other minorities (95% CI [0.4 years, not estimated]) (p = 0.28). There was no significant difference in mortality based on insurance type or gender for either type of transplant. There was a significant difference in mortality for allogenic transplant patients based on average median household income when compared at an average income of $60,000/ year (OR 2.6, 95% CI [1.164, 5.6] p = 0.0097). Conclusions: Overall survival for AYA patients who had a transplant for any indication at our institution was better than expected. There were no significant differences for either transplant type based on gender, racial/ethnic background, gender, age, or indication for transplant. There was a significant difference based on median household income. Larger multi-institutional studies are likely needed to accurately identify further demographic disparities.
Effect of the killing style of individual CAR T cells on the clinicopathological behavior of therapeutic products in the clinic.
Authors: Ahmed Z Gad, Jessica S Morris, Lea Godret-Miertschin, Melisa J Montalvo, Harrison Berger, Rebecca M Brock, Kristen Fousek, Madhuwanti Srinivasan, Arash Saeedi, Kandice Levental, Maksim Mamonkin, Alexandre Carisey, Navin Varadarajan, Meenakshi Hegde, Sujith Joseph, Ilya Levental, Malini Mukherjee, Nabil Ahmed
Journal: Journal of Clinical Oncology (2023)

2548 Background: CAR T cell products that signal through CD28 and 41BB are highly effective against B lineage leukemia, despite exhibiting distinct efficacy and toxicity profiles in patients. Specifically, CD28 has been linked to higher upfront lytic activity and toxicity, while 41BB induces longer CAR T cell persistence and more durable progression free survival. We reasoned that the killing style of individual CAR T cells can explain the clinicopathological behavior of CAR T cell products in the clinic. Methods: We studied the cellular kinetics of CD28 and 41BB signaling CD19 CAR T cell products approved in the clinic, their single cell killing behavior in high throughput, the molecular composition of the lipid rafts inside the CAR immune synapse (CARIS) they form with their target cells, and their CARIS mechanical properties, then corroborated these findings in one kinetic model to explain their distinct clinicopathological behavior in the clinic. Results: We discovered that tumor encounter polarizes CD28 CAR T cell products to a predominance of more differentiated CD8 effectors that rely on short-lived highly lethal synapses with tumor cells. CD28 CAR T cell mediated synapses are characterized by fast mechanical buildup and resolution and brisk shuttling of CAR and other associated molecules into the CARIS and rapid polarization of the killing machinery in a manner that supports a mastery of serial killing mediated by perforin and granzymes. In contrast, 41BB responds to tumor stimulation by a T h2 -polarizing cytokine milieu that robustly expands a balanced CD4/CD8 population of effectors preserving a central memory phenotype. 41BB CAR T cells engage in lengthier synapses characterized by slower accumulation of CAR molecules in a mechanically tonic CARIS and rather collaborative yet lengthy Fas ligand-mediated killing process. Conclusions: We show here that CAR T cell signaling domains mediate distinct killing dynamics that can explain their behavior in patients. By understanding and potentially modulating these dynamics, the CAR T cell functionality and toxicity can be rationally optimized.
Adjuvant chemotherapy after surgical resection of colorectal metachronous metastases: A phase II nonrandomized trial.
Authors: Sevindzh Evdokimova, Anna Kornietskaya, Larisa Bolotina, Dmitriy Sidorov, Andrey Kaprin
Journal: Journal of Clinical Oncology (2023)

e15597 Background: Currently, six months of perioperative or adjuvant chemotherapy (ACT) is a standard treatment option after radical surgical removal of metachronous metastases in patients with metastatic colorectal cancer (CRC). Data show that ACT improves relapse-free survival in such patients, although no difference in overall survival rate was observed. We conducted a non-randomized trial to examine the efficacy of ACT after radical resection of metachronous metastases from CRC. Methods: Patients older 18 years old and more with confirmed CRC and any site of resectable metachronous metastases were assigned to either surgery alone or adjuvant mFOLFOX6 for 6 months. The primary end point was 2-year disease-free survival (DFS). Results: Between June 2008 and September 2022, 123 patients were assigned to surgery alone group (51 patients) or ACT after surgery (72 patients). At a median follow-up of 27.0 months (20.9-33.1), 2-year DFS was 54.2% in surgery alone group versus 45.5% in ACT group. Median DFS (mDFS) was 25.5 months (95% CI 9.8 – 41.2) in surgery alone group versus 20.9 months (95% CI 13.5 – 28.4) in systemic chemotherapy (HR 0.75; 95% CI 0.45-1.25, P = 0.26). Conclusions: ACT didn’t improve DFS among patients after radical surgical resection of metachronous metastases from CRC.
A prospective analysis of robotic three-stage esophagectomy for carcinoma of the esophagus in a tertiary care cancer centre.
Authors: Udayee Teja Bathala
Journal: Journal of Clinical Oncology (2023)

e16078 Background: This study is to evaluate the safety and technical feasibility of total robot-assisted three-stage esophagectomy in terms of: Completeness of surgery, margin status, lymph nodes harvested, learning curve, docking time and total operating time, and associated morbidity and mortality. Methods: It is a prospective non-randomised study from Nov 2016 to Nov 2022 with a total of 168 patients. Inclusion criteria: Histologically proven squamous cell carcinoma, adenocarcinoma of the intrathoracic esophagus surgically resectable (T1-3,N0 -1,M0); ECOG performance status: 0,1 or 2. Exclusion criteria: Carcinoma of cervical esophagus; patients unfit for general anesthesia; stage IV disease. Results: In a total of 168 patients, 52% had Squamous cell carcinoma and 48% had Adenocarcinoma; 8% had upper thoracic, 44.5% mid thoracic and 47% lower thoracic lesions. Mean docking time of 33 mins and mean operating time of 321 min. Average hospital stay of 7 days with average of 44 lymph nodes retrieved and mean blood loss of 280 ml. Intra operative complications of RLN injury in 2%, Thoracic duct injury in 1.6%, and Azygous vein injury in 1%.Post operative complications such as delayed gastric emptying in 3.5%, anastomotic leak in 2.9%, pleural effusion in 2.4%, wound infection in 0.6% and re-exploration in 1.7%. Conclusions: Robotic-assisted esophagectomy has its own unique benefits of very low conversion rates, short learning curve, good quality lymphadenectomy in supra-azygous and bilateral recurrent laryngeal nerve area, less painful with faster recovery even in aged patients with significant co-morbidities. Future RCT may confirm the lower incidence of major complications, and similar OS and DFS compared to open approaches.[Table: see text][Table: see text]
Dostarlimab for primary advanced or recurrent (A/R) endometrial cancer (EC): Outcomes by blinded independent central review (BICR) of the RUBY trial (ENGOT-EN6-NSGO/GOG-3031/RUBY).
Authors: Matthew A. Powell, Sakari Hietanen, Robert L. Coleman, Bradley J. Monk, Oleksandr Zub, David M. O'Malley, Lucy Gilbert, Iwona Podzielinski, Roberto Angioli, Dana Meredith Chase, Dirk Bauerschlag, Destin Black, Annemarie Thijs, Sudarshan Sharma, Michael A. Gold, Kari L Ring, Zangdong He, Shadi Stevens, Brian M. Slomovitz, Mansoor R. Mirza
Journal: Journal of Clinical Oncology (2023)

5503 Background: RUBY (NCT03981796) evaluated the efficacy and safety of the anti–programmed death 1 (PD-1) dostarlimab + standard of care (SOC) carboplatin paclitaxel (CP) versus CP alone in A/R EC. The primary endpoint of PFS by investigator assessment (INV) per RECIST v1.1 was significantly longer with dostarlimab+CP than placebo (PBO)+CP in the mismatch repair deficient/microsatellite instability-high (dMMR/MSI-H; HR 0.28; 95% CI 0.162–0.495) and overall populations (HR 0.64, 95% CI 0.507–0.800). Here we present secondary efficacy endpoints by BICR. Methods: RUBY is a phase 3, global, randomized, double-blind, multicenter, PBO-controlled study. Patients (pts) with primary advanced stage III or IV or first recurrent EC were randomized 1:1 to receive dostarlimab 500 mg, or PBO, plus carboplatin AUC 5 and paclitaxel 175 mg/m 2 Q3W (6 cycles), followed by dostarlimab 1000 mg, or PBO, monotherapy Q6W for up to 3 y. Secondary endpoints by BICR assessment per RECIST v1.1 were PFS, ORR, DOR, and DCR in the overall and dMMR/MSI-H populations. Results: 494 pts were randomized (245:dostarlimab+CP; 249:PBO+CP); 47.8% had recurrent disease, 18.6% and 33.6% had primary stage III and IV disease, respectively. PFS by BICR was longer with dostarlimab+CP than PBO+CP in the dMMR/MSI-H (HR 0.29; 95% CI 0.158–0.543) and overall populations (HR 0.66; 95% CI 0.517–0.853; Table). Consistent benefits were seen with dostarlimab+CP for ORR, DCR, and DOR by BICR in the dMMR/MSI-H and overall populations (Table). Safety was previously reported. Conclusions: Dostarlimab+CP showed clinically meaningful improvement in BICR-assessed PFS in the dMMR/MSI-H and overall populations compared with CP alone. The HRs for PFS per BICR and per INV were consistent, which supports the reliability of PFS by INV in EC trials. Benefits were seen in all BICR-assessed endpoints, which were consistent with INV. Dostarlimab+CP represents a new SOC for pts with primary A/R EC. Clinical trial information: NCT03981796 . [Table: see text]
Effect of doxorubicin on efficacy of immune checkpoint inhibitors through increasing infiltration of CD8-positive T cells and activating STAT1-IRF1-CXCL10 axis.
Authors: Qiao Xiaosu, Duancheng Guo, Zhonghua Tao, Xichun Hu
Journal: Journal of Clinical Oncology (2023)

e13095 Background: Immune checkpoint inhibitors (ICIs) generate an enduring clinical remission in metastatic cancers. However, the efficacy of ICIs monotherapy for triple negative breast cancer (TNBC) is limited. Strategies are urgently needed to enhance anticancer immune responses in TNBC to prolong survival of patients. Methods: BALB/c mice subcutaneous tumor experiments were done to evaluate the efficacy of doxorubicin combined with PD-1 inhibitor, compared with other chemotherapy including cisplatin and paclitaxel. RNA-seq and single-sample gene set enrichment analysis (ssGSEA) were done with our collected mice tumor tissue to observe changes of tumor immune environment in TNBC after chemotherapy combined with immunotherapy. Then, we performed coculture, Transwell assay and FACs in TNBC cell lines, including MDA-MB-231, BT549 and 4T1, and primary CD8 + T cells, to assess effects of doxorubicin on CD8 + T cell migration in vitro. Gene Ontology (GO) and Kyoto Encyclopedia of Genes, Genomes (KEGG) analysis were enriched from RNA-seq data to seek for a pathway. We analyzed the difference of CD8 + T cell infiltration related gene expression, including CCL2, CCL3, CCL4, CCL5, CXCL9, CXCL10, CXCL11. Western blot, qPCR and ELISA were utilized to explore possible mechanism in stronger migration of CD8 + T cells by doxorubicin. Rescue assays were used to confirm the involved mechanisms. Results: Subcutaneous tumor experiment showed that doxorubicin could enhance the efficacy of immune checkpoint inhibitors (p＜0.05),andthe immune microenvironment in TNBC transferred from "anti-inflammatory" to "proinflammatory" status after doxorubicin combined with immunotherapy, compared with other chemotherapy drugs combined with immunotherapy. Higher CD8 + T cells infiltration occurred in TNBC treated with doxorubicin in vivo (p＜0.05). The CD8 + T cells migration assay demonstrated a higher CD8 + T cell migration with doxorubicin in vitro (p＜0.05). KEGG analysis revealed that the chemokine-related pathway was significantly activated after doxorubicin treatment, in which CXCL10 chemokine was most likely to be responsible for CD8 + T cell infiltration based on its expression and secretion (both p&lt;0.01). Further experiments demonstrated that the expression of the whole STAT1-IRF1-CXCL10 axis was up-regulated in TNBC mice treated with doxorubicin (p＜0.01), and the STAT1-IRF1-CXCL10 axis was also activated in doxorubicin-treated TNBC cell lines (p＜0.0001). Conclusions: This research demonstrated that doxorubicin can enhance efficacy of immune checkpoint inhibitors through increasing infiltration of CD8 + T cells in triple-negative breast cancer via activating STAT1-IRF1-CXCL10 axis. These results provide rationales of doxorubicin combined with PD-1 inhibitor for extending survival of TNBC patients.
Associations of diet with survival of patients (pts) with metastatic cancer of the urothelium (mUC) and renal cell carcinoma (mRCC) on immune checkpoint blockade (ICB).
Authors: Brendan John Guercio, Neha Ratna, David Gavrilov, Cihan Duzgol, Mahnoor Akhlaq, Min Yuen Teo, Ashley M Regazzi, Ritesh R Kotecha, Samuel A Funt, David H Aggen, Martin H Voss, Maria Isabel Carlo, Andrew Leonard Laccetti, Darren R. Feldman, Neil J. Shah, Robert J. Motzer, Dean F. Bajorin, Jonathan E. Rosenberg, Gopa Iyer, Chung-Han Lee
Journal: Journal of Clinical Oncology (2023)

4598 Background: The gut microbiome is an emerging modifiable predictor of ICB efficacy. Diet impacts the gut microbiome and fiber intake is associated with longer progression-free survival (PFS) in advanced melanoma treated with ICB. Whether diet impacts ICB benefit in mUC or mRCC remains unknown. Methods: Using a prospective cohort design, baseline dietary data were collected from pts with mUC or mRCC initiating ICB at Memorial Sloan Kettering Cancer Center using the extensively validated Harvard Willett Food Frequency Questionnaire. Tumor mutational burden (TMB) was estimated by next generation sequencing (MSK-IMPACT). The primary endpoint was radiologist assessed PFS, with secondary endpoint of overall survival (OS). Fiber intake was stratified as high or low using the median intake in our cohort. Associations between fiber intake and clinical outcomes were assessed using Kaplan-Meier curves plus univariable (UV) and multivariable (MV) Cox proportional hazards regression. Models were adjusted for prior ICB exposure. Models for mUC controlled for TMB and Bellmunt risk factors. Models for mRCC controlled for histology (clear vs non-clear cell) and IMDC risk score. Results: From 2/2021-6/2022, 88 pts eligible for analysis were enrolled with median follow-up of 10.1 months (mo) (mUC n = 40; mRCC n = 48). Median fiber intake was 17.5 g/day (interquartile range 12.5-24.5). Among pts with mUC, high fiber intake (≥17.5 g/day) was associated with longer PFS (UV hazard ratio [HR] 0.56, 95% CI 0.26-1.19, p = .13; MV HR 0.39, 95% CI 0.16-0.93, p = .03). Similar trends were observed for mRCC. In subgroup analyses, PFS was numerically longer with high fiber intake among mUC pts on maintenance avelumab (median PFS 6.1 vs 3.0 mo, n = 14) and in pts with mRCC treated with first-line (1L) ipilimumab + nivolumab (median PFS 18.0 vs 5.7 mo, n = 14) and 1L ICB + tyrosine kinase inhibitor (median PFS not reached vs 5.1 mo, n = 21). Among pts with mUC on non-maintenance ICB, pts with high fiber intake had numerically higher PFS at 6 mo (38% vs 14%, n = 26). Conclusions: This pilot study indicates that high fiber intake is associated with longer PFS among pts with mUC on ICB. Trends towards longer PFS and OS with high fiber intake were observed among pts with mRCC. Analyses of the gut microbiome are underway to investigate mechanisms of action. [Table: see text]
Phase 2 study of batiraxcept (AVB-S6-500, an AXL inhibitor) as monotherapy, in combination with cabozantinib (cabo), and in combination with cabo and nivolumab (nivo) in patients with advanced clear cell renal cell carcinoma (ccRCC).
Authors: Katy Beckermann, Matthew T Campbell, Naomi B. Haas, Moshe Chaim Ornstein, Xin Gao, Shifeng S. Mao, Hans J. Hammers, Saby George, Ariel Ann Nelson, Theodore Stewart Gourdin, Holavanahalli Keshava-Prasad, Arif Hussain, Christopher J. Hoimes, Hongxia Yan, Vanessa Esquibel, Gail McIntyre, Robert B. Geller, Martin H Voss, Brian I. Rini, Neil J. Shah
Journal: Journal of Clinical Oncology (2023)

4534 Background: AXL is up-regulated by hypoxia-inducible factor-1 signaling in VHL-deficient tumor cells, playing a critical role in metastasis and resistance to VEGF-targeted therapies. Batiraxcept is a recombinant fusion protein containing an extracellular region of AXL combined with the human immunoglobulin G1 heavy chain (Fc), demonstrating potent and specific AXL inhibition through competitive binding of its ligand GAS6. A prior Phase 1b study showed promising outcomes for batiraxcept + cabo combination in patients who had failed first line (1L) therapy. Methods: This trial tested batiraxcept 15 mg/kg every 2 weeks (q2w) in 3 cohorts of ccRCC patients: 1) batiraxcept monotherapy (n=10) in patients with relapsing disease and no curative options; 2) batiraxcept + cabo 60 mg daily (QD) in patients with at least 1 prior therapy (n=25); and 3) batiraxcept + cabo 40 mg QD and nivo 240 q2w or 480 mg q4w in 1L (n=11). Primary endpoint was investigator assessed objective response rate (ORR) by RECIST v1.1, and key secondary endpoints were safety, progression free survival (PFS), and overall survival. Results: Enrollment has completed as of 17-January-2023. In the 3 cohorts, IMDC intermediate + poor risk was 80%, 76%, and 27%, and median prior lines of therapy were 4, 2, 0. Prior immunotherapy (IO) was received by 100%, 88%, and 0% patients. One hundred percent of patients receiving monotherapy and 40% of 2L patients receiving batiraxcept + cabo had received prior VEGF-TKIs. We describe efficacy and safety across the 3 cohorts. Conclusions: Batiraxcept monotherapy was well tolerated but had limited clinical activity. Batiraxcept-based combinations demonstrated efficacy and tolerability. Given encouraging safety and efficacy signals, batiraxcept + cabo will be further studied in a phase 3 trial of 2L+ ccRCC patients whose disease has progressed on prior IO and VEGF-TKI treatment. Exploratory analysis for a baseline serum soluble AXL/GAS6 ratio biomarker was found to have predictability for clinical activity in the phase 1b study evaluating batiraxcept + cabo in patients who had failed 1L therapies; a similar analysis using the biomarker is ongoing for this patient population. Clinical trial information: NCT04300140 . [Table: see text]
Cost-effectiveness analysis of a circulating tumor DNA-based molecular residual disease assay to guide adjuvant chemotherapy decisions in patients with resectable early stage colorectal cancer.
Authors: John Schneider, Ryan Bresnahan, Nadine Chami, Muriel Brackstone, Malek B. Hannouf
Journal: Journal of Clinical Oncology (2023)

e18929 Background: An ongoing prospective study in patients with stage II or III colorectal cancer (CRC) has demonstrated ctDNA testing to be prognostic of recurrence risk and predictive of adjuvant chemotherapy (ACT) benefit. From the perspective of a US payer, we aimed to investigate the cost effectiveness of incorporating ctDNA analysis using the commercially available molecular residual disease (MRD) assay (Signatera™) into standard practice to aid in adjuvant chemotherapy decision-making, where traditional high-risk clinicopathological (CP) features have not shown a significant benefit of ACT in Stage II CRC. Methods: We developed a decision model to project lifetime clinical and economic consequences of different adjuvant treatment-guiding strategies. The model was parameterized using a follow-up of up to 2-years from a recently published data from GALAXY study and the cost data from the US literature. GALAXY is an observational arm of the ongoing CIRCULATE-Japan study (UMIN000039205) that analysed pre-surgical and post-surgical ctDNA in patients with stage II-IV resectable CRC. Costs are presented in 2023 US dollars. Future costs and benefits were discounted at 3%. Results: Compared to the CP predictors alone-based strategy, ctDNA analysis using the MRD assay in combination with CP predictors-based strategy led to an increase of 0.8 life years and 0.7 quality adjusted-Life Years (QALY) and cost savings of $9,771 per patient. Conclusions: The addition of MRD detection by ctDNA to traditional CP predictors aids in adjuvant chemotherapy decision-making in patients with stage II or III resectable CRC and is likely to be cost effective in the US healthcare system. ctDNA testing should therefore be considered for adoption in this disease setting.